• [The contribution of epidemiological models to the description of the outbreak of the COVID-19 pandemic].

      Priesemann, Viola; Meyer-Hermann, Michael; Pigeot, Iris; Schöbel, Anita; HZI,Helmholtz-Zentrum für Infektionsforschung GmbH, Inhoffenstr. 7,38124 Braunschweig, Germany. (Springer, 2021-07-30)
      After the global outbreak of the COVID-19 pandemic, an infection dynamic of immense extent developed. Since then, numerous measures have been taken to bring the infection under control. This was very successful in the spring of 2020, while the number of infections rose sharply the following autumn. To predict the occurrence of infections, epidemiological models are used. These are in principle a very valuable tool in pandemic management. However, they still partly need to be based on assumptions regarding the transmission routes and possible drivers of the infection dynamics. Despite numerous individual approaches, systematic epidemiological data are still lacking with which, for example, the effectiveness of individual measures could be quantified. Such information generated in studies is needed to enable reliable predictions regarding the further course of the pandemic. Thereby, the complexity of the models could develop hand in hand with the complexity of the available data. In this article, after delineating two basic classes of models, the contribution of epidemiological models to the assessment of various central aspects of the pandemic, such as the reproduction rate, the number of unreported cases, infection fatality rate, and the consideration of regionality, is shown. Subsequently, the use of the models to quantify the impact of measures and the effects of the "test-trace-isolate" strategy is described. In the concluding discussion, the limitations of such modelling approaches are juxtaposed with their advantages.
    • On the Impact of Chemo-Mechanically Induced Phenotypic Transitions in Gliomas.

      Mascheroni, Pietro; López Alfonso, Juan Carlos; Kalli, Maria; Stylianopoulos, Triantafyllos; Meyer-Hermann, Michael; Hatzikirou, Haralampos; HZI,Helmholtz-Zentrum für Infektionsforschung GmbH, Inhoffenstr. 7,38124 Braunschweig, Germany. (MPDI, 2019-05-24)
      Tumor microenvironment is a critical player in glioma progression, and novel therapies for its targeting have been recently proposed. In particular, stress-alleviation strategies act on the tumor by reducing its stiffness, decreasing solid stresses and improving blood perfusion. However, these microenvironmental changes trigger chemo–mechanically induced cellular phenotypic transitions whose impact on therapy outcomes is not completely understood. In this work we analyze the effects of mechanical compression on migration and proliferation of glioma cells. We derive a mathematical model of glioma progression focusing on cellular phenotypic plasticity. Our results reveal a trade-off between tumor infiltration and cellular content as a consequence of stress-alleviation approaches. We discuss how these novel findings increase the current understanding of glioma/microenvironment interactions and can contribute to new strategies for improved therapeutic outcomes. View Full-Text
    • Permissive selection followed by affinity-based proliferation of GC light zone B cells dictates cell fate and ensures clonal breadth.

      Nakagawa, Rinako; Toboso-Navasa, Amparo; Schips, Marta; Young, George; Bhaw-Rosun, Leena; Llorian-Sopena, Miriam; Chakravarty, Probir; Sesay, Abdul Karim; Kassiotis, George; Meyer-Hermann, Michael; et al. (National Academy of Sciences, 2021-01-12)
      Affinity maturation depends on how efficiently germinal centers (GCs) positively select B cells in the light zone (LZ). Positively selected GC B cells recirculate between LZs and dark zones (DZs) and ultimately differentiate into plasmablasts (PBs) and memory B cells (MBCs). Current understanding of the GC reaction presumes that cMyc-dependent positive selection of LZ B cells is a competitive affinity-dependent process; however, this cannot explain the production of GC-derived lower-affinity MBCs or retention of GC B cells with varied affinities. Here, by combining single-cell/bulk RNA sequencing and flow cytometry, we identified and characterized temporally and functionally distinct positively selected cMyc+ GC B cell subpopulations. cMyc+ LZ B cell subpopulations enriched with either higher- or lower-affinity cells diverged soon after permissive positive selection. The former subpopulation contained PB precursors, whereas the latter comprised less proliferative MBC precursors and future DZ entrants. The overall affinity of future DZ entrants was enhanced in the LZ through preferential proliferation of higher-affinity cells. Concurrently, lower-affinity cells were retained in GCs and protected from apoptosis. These findings redefine positive selection as a dynamic process generating three distinct B cell fates and elucidate how positive selection ensures clonal diversity for broad protection.
    • Staphylococcus aureus Alpha-Toxin Limits Type 1 While Fostering Type 3 Immune Responses.

      Bonifacius, Agnes; Goldmann, Oliver; Floess, Stefan; Holtfreter, Silva; Robert, Philippe A; Nordengrün, Maria; Kruse, Friederike; Lochner, Matthias; Falk, Christine S; Schmitz, Ingo; et al. (Frontiers, 2020-08-07)
      Staphylococcus aureus can cause life-threatening diseases, and hospital- as well as community-associated antibiotic-resistant strains are an emerging global public health problem. Therefore, prophylactic vaccines or immune-based therapies are considered as alternative treatment opportunities. To develop such novel treatment approaches, a better understanding of the bacterial virulence and immune evasion mechanisms and their potential effects on immune-based therapies is essential. One important staphylococcal virulence factor is alpha-toxin, which is able to disrupt the epithelial barrier in order to establish infection. In addition, alpha-toxin has been reported to modulate other cell types including immune cells. Since CD4+ T cell-mediated immunity is required for protection against S. aureus infection, we were interested in the ability of alpha-toxin to directly modulate CD4+ T cells. To address this, murine naïve CD4+ T cells were differentiated in vitro into effector T cell subsets in the presence of alpha-toxin. Interestingly, alpha-toxin induced death of Th1-polarized cells, while cells polarized under Th17 conditions showed a high resistance toward increasing concentrations of this toxin. These effects could neither be explained by differential expression of the cellular alpha-toxin receptor ADAM10 nor by differential activation of caspases, but might result from an increased susceptibility of Th1 cells toward Ca2+-mediated activation-induced cell death. In accordance with the in vitro findings, an alpha-toxin-dependent decrease of Th1 and concomitant increase of Th17 cells was observed in vivo during S. aureus bacteremia. Interestingly, corresponding subsets of innate lymphoid cells and γδ T cells were similarly affected, suggesting a more general effect of alpha-toxin on the modulation of type 1 and type 3 immune responses. In conclusion, we have identified a novel alpha-toxin-dependent immunomodulatory strategy of S. aureus, which can directly act on CD4+ T cells and might be exploited for the development of novel immune-based therapeutic approaches to treat infections with antibiotic-resistant S. aureus strains.